Skeletal muscle tissue is often required in reconstructive craniofacial surgery following trauma, resection due to cancer, or correction of genetic defects. The long-term goal of the applicants' research is to regenerate functional craniofacial skeletal muscle. While there has been significant success in the field to date in young animals with cell transplantation strategies, the environment in aged animals severely limits the potential of cells to drive regeneration. Further, the need to isolate and then transplat muscle stem cells greatly limits the clinical practicality of current muscle regeneration strategie. The specific hypothesis guiding this application is that biomaterials may be used to provide an environment conducive to the proliferation of both transplanted and host satellite cell recruited t the biomaterial, even in aged mice, and their participation in muscle regeneration. The hypothesis will be addressed with the following aims: (1) Develop and examine the ability of biomaterial vehicles to create a new microenvironment conducive to the proliferation and participation in regeneration of transplanted satellite cells, in young and aged mice. (2) Develop biomaterial vehicles capable of being externally actuated with magnetic fields, and examine their ability to allow cell release on-demand in order to enhance regeneration with transplanted satellite cells. (3) Develop biomaterials to recruit host satellite cells from the damaged muscle o aged mice, promote their proliferation within the device, and release the daughter cells on-demand to participate in muscle regeneration. The successful completion of these aims will lead to new strategies for the regeneration and return to function of damaged muscle tissue. This work will have significant applications in craniofacial reconstructive surgery involving the regeneration of small craniofacial muscles, and will likely apply to the regeneration of muscle throughout the body. The proposed studies will also lead to the development of new biomaterials that enable passive and active release of cells to drive regeneration, and an improved understanding of how environmental cues regulate muscle stem cell activation, proliferation, and participation in regeneration. PHS 398/2590 (Rev. 09/04) Page Continuation Format Page PUBLIC HEALTH RELEVANCE: Skeletal muscle tissue is often required in reconstructive craniofacial surgery following trauma, resection due to cancer, or correction of genetic defects. This project proposes a new approach to muscle regeneration, and specifically addresses the diminished regeneration ability seen in people with age. Success in these studies will provide an important step in translating tissue regeneration strategies out of the lab and into the clinic.